Gene x environment interactions on brain and behaviour in the Cacna1c genetic rat model: Calcium signalling, microRNAs, and immune activation

Cacna1c 遗传大鼠模型中基因 x 环境对大脑和行为的相互作用：钙信号传导、microRNA 和免疫激活

• 批准号: 250951389
• 负责人: Professor Dr. Rainer K.W. Schwarting
• 金额: --
• 依托单位: Abteilung Verhaltensneurowissenschaft
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/250951389?language=en
• 关键词: Gene; environment; interactions; brain; behaviour

Affective disorders (AD), i.e. major depressive disorder (MDD) and bipolar disorder (BD), are phenotypes to which genetic and environmental risk factors contribute. The underlying neurobiological mechanisms by which such factors interact and how they exert their influence on brain structure and function are yet poorly understood. WP2, animal backbone of the FOR2107, addresses these questions by applying a gene x environment (GxE) approach in the Cacna1c genetic rat model. In the first funding period, we obtained substantial evidence for multiple behavioural alterations in Cacna1c+/- rats, including elevated anxiety-related behaviour, deficits in pre-pulse inhibition of acoustic startle under apomorphine challenge, reversal learning impairments in a spatial navigation task, and social behaviour and acoustic communication deficits. Of particular relevance for BD, the effectiveness of lithium in inhibiting mania-like phenotypes evoked by amphetamine was almost blunted in Cacna1c+/- rats. Environmental modulation of behavioural phenotypes was paralleled by GxE interactions at the level of neurobiological measures, immune activation, and epigenetic modifications. For instance, a widespread reduction in mature microRNA (miRNA) levels was detected in the hippocampus of Cacna1c+/+ rats in response to post-weaning social isolation (SI), as a model of maltreatment. Intriguingly, this effect was largely blunted in Cacna1c+/- rats. Specifically, the vast majority of miRNAs (>80%) was affected by the GxE interaction, indicating that most hippocampal miRNAs are subject to regulation by a combination of genetic and environmental factors (collab. WP3). Moreover, while post-weaning SI evoked immune reactivity characterized by elevated pro-inflammatory cytokines in Cacna1c+/+ rats, no such reactivity was seen in Cacna1c+/- rats, suggesting resilience (collab. WP4). In the second funding period, we will follow five lines of research in our established GxE Cacna1c rat model. We will (1) identify biopsychological mechanisms underlying social behaviour and acoustic communication deficits; (2) develop a novel behavioural assay for BD-like affective cycling; and (3) link alterations in calcium signalling components in prefrontal cortex and hippocampus to behavioural phenotypes with relevance to AD. Together with WP3, we will (4) further explore the impact of miRNA manipulations in prefrontal cortex and hippocampus by means of intracerebral injection of recombinant adeno-associated virus particles (rAAV), with the aim to rescue behavioural phenotypes relevant to AD after post-weaning SI through restoring miRNA biogenesis. Finally, with WP3 and WP4, we will (5) assess the impact of such miRNA biogenesis manipulations on immune signatures and, vice versa, the impact of immune challenges on AD-relevant phenotypes. Through this highly interconnected approach, the project promises novel insight regarding miRNA biogenesis and immune system in AD aetiology and treatment.

情感障碍（AD），即重度抑郁症（MDD）和双相情感障碍（BD），是遗传和环境风险因素促成的表型。这些因素相互作用的潜在神经生物学机制以及它们如何对大脑结构和功能产生影响，目前还知之甚少。WP 2是FOR 2107的动物骨架，通过在Cacna 1c遗传大鼠模型中应用基因x环境（GxE）方法来解决这些问题。在第一个资助期内，我们获得了Cacna 1c +/-大鼠多种行为改变的大量证据，包括焦虑相关行为升高、阿扑吗啡激发下声惊吓的前脉冲抑制缺陷、空间导航任务中的逆转学习障碍以及社会行为和声学沟通缺陷。与BD特别相关的是，在Cacna 1c +/-大鼠中，锂抑制安非他明诱发的躁狂样表型的有效性几乎减弱。环境调节的行为表型是由GXE相互作用在神经生物学措施，免疫激活，和表观遗传修饰的水平。例如，在Cacna 1c +/+大鼠的海马中检测到成熟microRNA（miRNA）水平的广泛降低，以响应断奶后的社会隔离（SI），作为虐待的模型。有趣的是，这种效应在Cacna 1c +/-大鼠中很大程度上被减弱。具体地，绝大多数miRNA（>80%）受GxE相互作用的影响，表明大多数海马体miRNA受到遗传和环境因素的组合的调节（collab. WP 3）。此外，虽然断奶后SI在Cacna 1c +/+大鼠中诱发了以升高的促炎细胞因子为特征的免疫反应性，但在Cacna 1c +/-大鼠中未观察到此类反应性，表明了恢复力（collab. WP 4）。在第二个资助期内，我们将在我们建立的GxE Cacna 1c大鼠模型中进行五项研究。我们将（1）确定社会行为和声学沟通缺陷的生物心理学机制;（2）开发一种新的BD样情感循环行为测定法;（3）将前额叶皮层和海马中钙信号成分的改变与AD相关的行为表型联系起来。与WP 3一起，我们将（4）通过脑内注射重组腺相关病毒颗粒（rAAV）进一步探索miRNA操纵在前额叶皮层和海马中的影响，目的是通过恢复miRNA生物合成来挽救断奶后SI后与AD相关的行为表型。最后，利用WP 3和WP 4，我们将（5）评估这种miRNA生物发生操作对免疫特征的影响，反之亦然，评估免疫挑战对AD相关表型的影响。通过这种高度相互关联的方法，该项目有望在AD病因学和治疗中对miRNA生物发生和免疫系统提出新的见解。